insulin treatment for type 2 diabetes management

INSULIN TREATMENT FOR TYPE 2 DIABETES MANAGEMENT

APIRADEE SRIWIJITKAMOL

DIVISION OF ENDOCRINOLOGY AND METABOLISM

DEPARTMENT OF MEDICINE

FACULTY OF MEDICINE SIRIRAJ HOSPITOL

QUESTION 1

1. ทา่นเคยเป็นแพทยค์นแรกทีเ่ริม่ใหอ้นิสลุนิรักษาในผู ้เป็นเบาหวานทีม่าตรวจที ่OPD หรอืไม ่

A. YES

B. NO

Breakfast Lunch Dinner

S L E E P

Insulin

Level

“Prandial” Insulin

“Basal” Insulin

Normal Secretory Pattern of Insulin

Total daily insulin requirement = 0.5-1 unit/kg/D

The 50/50 Rule

Mrs B

60 years old Thai female

Type 2 DM Diagnosed 10 years ago

Co-morbid diseases: HT, Dyslipidemia

BW 60 kg.

Currently on

Glipizide 20 mg a day

Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea)

Her last HbA1C 9%, FPG 220 mg/dl

A. Lifestyle modification

B. Add TZD

C. Add AGI

D. Add DPP-IV inhibitor

E. Add insulin therapy

QUESTION 2 ทา่นจะใหก้ารรักษาผูป่้วยรายนี้อยา่งไร?

60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg

Currently on

Glipizide 20 mg a

day

Metformin 2000 mg

a day (used to on

2500 mg a day, but

had diarrhea)

Pioglitazone 30 mg

a day

Her last HbA1C 9%,

FPG 220 mg/dl

A. Continue OHA + NPH 6 u

B. Continue OHA + NPH 10 u

C. Off SU, Cont MET + NPH 10 u

D. Continue OHA + Glargine 10 u

E. Off OHA + Mix insulin 15 u bid

QUESTION 3 ถา้ทา่นเลอืกจะใหอ้นิสลุนิในผูป่้วยรายนี ้ทา่นจะเริม่ใหอ้ยา่งไร?

60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg

Currently on

Glipizide 20 mg a

day

Metformin 2000 mg

a day (used to on

2500 mg a day, but

had diarrhea)

Pioglitazone 30 mg

a day

Her last HbA1C 9%,

FPG 220 mg/dl

Oral Hypoglycemic agents failure

Add basal insulin

STUDY METHOD

700 T2DM

on OAD Add twice daily

biphasic insulin*

Add once (or twice)

daily basal insulin*

Add thrice daily

prandial insulin*

Randomisation

visit

One

year

* progress to more intensive insulin regimen only if clinically necessary † stop sulphonylurea if taken

Glycemic target: A1C ≤ 6.5%

R Add midday prandial insulin

if glycaemic target not met†

Add prandial insulin


Add basal insulin


Two

years

Three

years

Basal group

Biphasic group

Prandial group

4T Trial

Holman RR.N Engl J Med 2009;361:1736

0

20

40

60

80

HbA1C < 6.5% HbA1C < 7.0%

% Attainment of Target HbA1c

Basal group Biphasic group Prandial group

EFFICACY

4T Trial

0

2

4

6

8

Biphasic Prandial Basal

Body weigh gain (kg)

0

10

20

30

40

50

Biphasic Prandial Basal

%Hypoglycemia (mod to severe)

Basal group Biphasic group Prandial group

ADVERSE EFFECTS

4T Trial

STARTING WITH BASAL INSULIN ADVANTAGES

• 1 injection with no mixing

• Insulin pens for increased acceptance

• Slow, safe, and simple titration

• Low dosage

• Effective improvement in glycemic control

• Limited weight gain

6-37

BASAL INSULIN

•Which type?

• How to start?

• How to adjust?

Hours

Long (Glargine)

Intermediate (NPH)

Long (Detemir)

Insulin

Level

0 2 4 6 8 10 12 14 16 18 20 22 24

NPH insulin

Onset: 1 1/ 2 hr Peak: 4-12 hr Duration: 24 hr

Long-acting analogue insulin

Onset: 2-3 hr Peak: none Duration: 24 hr

TYPE OF BASAL INSULIN

TREAT-TO-TARGET TRIALS

Insulin glargine once-daily (evening)

NPH once-daily (evening)

Insulin continually titrated to target:

Fasting PG ≤100 mg/dl

n = 367

n = 389

Insulin detemir twice-daily

NPH twice-daily

Insulin continually titrated to target: Fasting and pre-dinner PG ≤ 108

mg/dl

n = 237

n = 238

Riddle et al 2003

Hermansen et al 2006

8.5

9.0

8.0

7.5

7.0

6.5

0 4 8 12 16 20 24

Hb

A1

c

(%

)

NPH + OAD

Glargine + OAD

Weeks

0

2

4

6

8

10

12

14

16

18

21% risk reduction p <0.02

42% risk reduction p <0.01

Overall Nocturnal Hypoglycaemia

Even

ts p

er p

ati

en

t p

er y

ear

-2 0 12 24

8.5

9.0

8.0

7.5

7.0

6.5

Weeks

NPH + OAD

Detemir + OAD

TREAT TO TARGET

Hermansen et al. Diabetes Care 2006;29: 1269

Riddle et al Diabetes Care 2003;26:3080-6.

Even

ts p

er p

ati

en

t p

er y

ear

0

2

4

6

8

10

12

14

16

18

Overall Nocturnal Hypoglycaemia

47% risk reduction

p < 0.001

55% risk reduction p < 0.001

Basal insulin

•Which type?

• How to start?

• How to adjust?

TREAT-TO-TARGET TRIALS

Insulin glargine once-daily (evening)

NPH once-daily (evening)

Insulin continually titrated to target:

Fasting PG ≤100 mg/dl

n = 367

n = 389

Insulin detemir twice-daily

NPH twice-daily

Insulin continually titrated to target: Fasting and pre-dinner PG ≤ 108

mg/dl

n = 237

n = 238

Riddle et al 2003

Hermansen et al 2006

The starting dose of both insulins was 10 IU

Starting doses were 10 units/IU.

If initial premeal PG <126 mg/dl

or BMI was <26.0 kg/m2,

starting doses were reduced to 6 units/IU.

Basal insulin

•Which type?

• How to start?

• How to adjust?

785 Insulin naive type 2 diabetes (A1C ≥8.0%)

Receiving 2 or 3 OHAs for ≥3 months

1.2.3 STUDY:

BASAL INSULIN

PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN

Davidson M et al. Endocr Pract 2011;17:395.

RUN-IN PHASE

Add Insulin glargine OD

14 weeks

A1C ≥7.0%

RANDOMIZATION

Basal insulin +

Prandial insulin 1 shot

Basal insulin +


Basal insulin +


ADD BASAL INSULIN

• Start BASAL INSULIN 10 unit

10.2

7.9

6.5

7.5

8.5

9.5

10.5

Baseline 14-wk run-in

HbA1c (%)

At 14-wk run-in 288/785 (37%) A1C < 7%

Maximum dose of Basal insulin

Increase insulin dose is associated with weight gain

Insulin dose <0.5 u/kg/D

decrease HbA1c 0.5% for each increment in insulin dose equal to 0.1 u/kg/D

Insulin dose >0.5 u/kg/D decrease HbA1c 0.5% for

each increment in insulin dose equal to 0.2 u/kg/D

Monnier L. Daibetes Metan 2006;32:7

TIP: BEDTIME INSULIN DAYTIME SULFONYLUREA

• Start NPH or non peak insulin 10 unit or

0.1-0.2 unit/kg at bedtime

• Continue Oral hypoglycemic agent

• Titrate

– If FPG > 110 mg/dl x 2D 2 unit • Keep FPG 90-110 mg/dl • Basal dose ~0.5-0.6 unit/kg/D (~50% of Total daily dose)


B. Add TZD

C. Add AGI




60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg

Currently on

Glipizide 20 mg a

day

Metformin 2000 mg

a day (used to on

2500 mg a day, but

had diarrhea)

Pioglitazone 30 mg

a day

Her last HbA1C 9%,

FPG 220 mg/dl

Efficacy of different OHAs

Class of

medicine

Expected decrease

in HbA1C

Biguanide 1.0 - 2.0%

Sulfonylureas 1.0 - 2.0%

Glinides* 0.5-1.5%

TZDs 0.5-1.4%

-glucosidase

inhibitors

0.5-0.8%

GLP-1 agonists 0.5-1.0%

DPP4 inhibitors 0.5-0.8%


B. Add TZD

C. Add AGI




60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg

Currently on

Glipizide 20 mg a

day

Metformin 2000 mg

a day (used to on

2500 mg a day, but

had diarrhea)

Pioglitazone 30 mg

a day

Her last HbA1C 9%,

FPG 220 mg/dl

A. Continue OHA + NPH 6 u

B. Continue OHA + NPH 10 u

C. Off SU, Cont MET + NPH 10 u

D. Continue OHA + Glargine 10 u

E. Off OHA + Mix insulin 15 u bid

QUESTION 3 ถา้ทา่นเลอืกจะใหอ้นิสลุนิในผูป่้วยรายนี ้ทา่นจะเริม่ใหอ้ยา่งไร?

60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg

Currently on

Glipizide 20 mg a

day

Metformin 2000 mg

a day (used to on

2500 mg a day, but

had diarrhea)

Pioglitazone 30 mg

a day

Her last HbA1C 9%,

FPG 220 mg/dl

Mrs B

Currently on

Glipizide 20 mg a day

Metformin 2000 mg a day

NPH 26 unit per day

Her last HbA1C 7.8%, FPG 100 mg/dl


B. Check insulin technique

C. Add TZD


E. Switch to Glargine 20 u


60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg

Currently on Glipizide 20 mg a

day Metformin 2000 mg

a day NPH 26 unit per

day Her last HbA1C 7.8%, FPG 100 mg/dl

A. Add TZD

B. Add DPP-IV inhibitor

C. Switch to Glargine 20 u

D. Add RI 4 u at big meal

E. Switch to Mix insulin 14 u bid


60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg





WHEN TO INTRODUCE MORE COMPLEX INSULIN REGIMENS?

• FPG is acceptable, but HbA1c is still high or post

prandial higher than goal

• When aggressive titration is limited by hypoglycemia

• In insulin deficiency end of type 2 diabetes spectrum maximum dose of basal insulin


Add basal insulin

Switch to Premixed Insulin

Add Prandial Insulin

ALL TO TARGET

STUDY DESIGN

3 m

B+P x3

+ met/TZD

A1C > 7

Premix x 2 + met and/or TZD

1 m

B+P x1

+ met/TZD

BASAL INSULIN

+ 2 OADs

3m

3 m

3 m

A1C > 7

A1C > 7

Current

OADs

B+P x2

+ met/TZD

BASAL + 1 PRANDIAL+ met and/or TZD

BASALINSULIN

+ 2 OADs

572 T2DM

2-3 OADs

A1C >7.5% @

screening

A1C >7% @

randomization

N=192

N=189

N=191

TTT • FPG and pre prandial BG < 100 mg/dl

• A1C <6.5%

Riddle MC and Rosenstock J et al. ADA 2011, San Diego.

60-week study

ALL TO TARGET

EFFICACY

A1C (%)

6.5

7.5

8.5

9.5

Premixed Basal +

1 shot

Basal +

0-3 shot

* *

* P < 0.05 vs. Premixed

39

49 45

14

0

20

40

60 *

24 *

*

24 *

Premixed Basal +

1 shot

Basal +

0-3 shot

% Patients with A1C <7%

Baseline <7% without hypo 60 weeks

ALL TO TARGET

SYMPTOMATIC HYPOGLYCEMIA

Event-rates per person-yr

Premixed Basal +

1 shot

Basal +

0-3 shot

* P < 0.05 vs. Premixed

0

5

10

15

*

*

*

*

BG < 70 mg/dl BG < 50 mg/dl

Basal + prandial Insulin had better efficacy and less hypoglycemia compare to Premixed


Add basal insulin



PRANDIAL INSULIN

0 2 4 6 8 10 12 14 16 18 20 22 24

Insulin

Level

Rapid (Lispro, Aspart, Glulisine)

Rapid-acting analogue insulin

Onset: <1/2 hr Peak: 1 hr Duration: 3-4 hr

Hours

Short (Regular)

Regular insulin Onset: 1/2 hr Peak: 1-3 hr Duration: 6-8 hr

785 Insulin naive type 2 diabetes (A1C ≥8.0%)

Receiving 2 or 3 OHAs for ≥3 months

1.2.3 STUDY:

BASAL INSULIN

PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN

Davidson M et al. Endocr Pract 2011;17:395.

RUN-IN PHASE

Add Insulin glargine OD

14 weeks

A1C ≥7.0%

RANDOMIZATION

Basal insulin +


Basal insulin +


Basal insulin +


1.2.3 STUDY:

BASAL INSULIN PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN

• Definition of Main meal

• Start: 1/10 of total daily dose of BASAL INSULIN

• Titration

– Preprandial SMBG during the preceeding 7

calendar days

– Weekly titration

A1C in all subjects (n=785) = 9.8 at run-in and 7.3 at randomization

Evolution of A1C in the randomized

Run in Randomization Wk 8 Wk 16 Wk 24

7.40

7.0

A1

Cc (%

)

10.19 10.19

10.16

7.44

7.29

8.0

9.0

10.0

PRANDIAL 1x

PRANDIAL 2x

PRANDIAL 3x

BASAL

(alone)

BASAL plus PRANDIAL

(patients with A1C >7%)

1.2.3 STUDY:


p=NS for all other pairwise comparisons

x1 x2 x3 0

1

2

3

4

5

Mean b

ody w

eig

ht

change

from

baselin

e (

kg)

3.7 3.8 3.9

PRANDIAL

0

5

10

15

20

x1 x2 x3 PRANDIAL

Confirm

ed s

ym

pto

matic h

ypo

(event/

patient-

year)

12.2

12.9

17.1

p=0.043

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Severe

or

serious h

ypo

(event/

patient-

year)

x1 x2 x3 PRANDIAL

0.10

0.30

0.26

1.2.3 STUDY:


Basal + 1, 2 or 3 prandial Insulin

had similar efficacy stepwise approach


Add basal insulin

Add Prandial insulin at main meal OR breakfast

TIPS: ADDING SINGLE PRANDIAL INSULIN INJECTION

• Add with the main meal

• Starting dose

– 10% of total daily dose, not less than 4 unit/meal

– Monitor pre-prandial glucose of next meal

– Target SMBG pre-prandial < 70-110 mg/dl,

bedtime 70-120 mg/dl

• Titration

dose , <10 u

dose, 10-20 u

dose, >20 u

add 1 unit

add 2 unit

add 3 unit

A. Add TZD

B. Add DPP-IV inhibitor

C. Switch to Glargine 20 u

D. Add RI 4 u at big meal

E. Switch to Mix insulin 14 u bid


60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg





Mrs B

Currently on

Metformin 2000 mg a day

NPH 30 unit per day

RI 10 unit at lunch time


A. Add RI 4 u at dinner

B. Switch to Mix insulin 15 u

bid

C. Switch to Mix insulin 20 u

at breakfast and 10 u at

dinner


60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg

Currently on Metformin 2000 mg a day NPH 30 unit per day RI 10 unit at lunch time



Add basal insulin



Premixed Insulin

• Human insulin 70/30

• Insulin analog 75/25

• Insulin analog 70/30

Mixtures of Pre-meal Insulin

Regular/NPH

Combined effect

B S L HS B

Insu

lin

Eff

ect

Starting dose?

• Usually conventional initial approach to dosing

premixed insulins in general practice is to prescribe

– a ratio of 2/3 of the total daily insulin dose in the

morning before breakfast

– and 1/3 in the evening before dinner.

PREMIXED INSULIN DOSING IN ACTUAL

PRACTICE: 2/3 IN AM, 1/3 IN PM, OR 50-50?

• retrospective, observational, descriptive study

was designed to examine the use of premixed

insulins in a community-based endocrinology practice

• to analyze the ratio, for morning and evening doses of premixed insulin. the premixed insulin dosing ratio of evening dose to TDD significantly differs from the standard value of 0.33 and is on average close to 0.5 or 50%

How about the SU, should we stop?

• The only consistent advantage of continue SU is:

– Reduced insulin dose requirements, which may

result in less daily injections

– Easier dose titration

– Improved compliance

• These potential benefits must be balanced against the side effects

Dose Titration

Blood Glucose Adjust Insulin*

Prebreakfast <70 mg/dL Decrease PM 1-2 U

140-250 mg/dL Increase PM 1-2 U

>250 mg/dL Increase PM 2-4 U

Presupper <70 mg/dL Decrease AM 1-2 U

140-250 mg/dL Increase AM 1-2 U

> 250 mg/dL Increase AM 2-4 U

Person J. Diabet Educat 2006;32:195

A. Add RI 4 u at dinner

B. Switch to Mix insulin 15 u

bid

C. Switch to Mix insulin 20 u

at breakfast and 10 u at

dinner


60 years old Thai

female

Type 2 DM Diagnosed

10 years ago

Co-morbid diseases:

HT, Dyslipidemia

BW 60 kg

Currently on Metformin 2000 mg a day NPH 30 unit per day RI 10 unit at lunch time


THANK YOU

insulin treatment for type 2 diabetes management

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